Asymmetric Synthesis and Enantiospecificity of Binding of 2‐(1,2,3,4‐Tetrahydro‐1‐isoquinolyl)‐ethanol Derivatives to μ and κ Receptors

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Abstract
A number of 2‐(1,2,3,4‐tetrahydro‐1‐isoquinolyl)‐ethanol derivatives 7a—e have been synthesized in diastereomerically and enantiomerically pure form and have been evaluated for their binding affinity at μ and κ opioid receptors. The amido ketones 5a—c and ent‐5a—c, which were accessible by employing 3b and ent‐3b for Asymmetric Electrophilic Amidoalkylation reactions, served as starting compounds. Upon reduction of 5a—c and ent‐5a—c the amido alcohols l‐6a—c, u‐6a—c, ent‐l‐6a—c and ent‐u‐6a—c were obtained. Hydrolysis of these compounds yielded the secondary amino alcohols l‐7a—c, u‐7a—c, ent‐l‐7a—c and ent‐u‐7a—c and upon reductive methylation of l‐7b—c, u‐7b—c, ent‐l‐7b—c and ent‐u‐7b—c with CH2O and NaCNBH3 the tertiary amino alcohols l‐7d—e, u‐7d—e, ent‐l‐7d—e and ent‐u‐7d—e were obtained.The binding affinities of the final compounds l‐7a—e, u‐7a—e, ent‐l‐7a—e and ent‐u‐7a—e at both the μ and the κ receptor were strongly dependent on their stereochemistry. In each case isomers exhibited higher affinity at the μ than at the κ receptor. For the secondary amino alcohols 7a—c the affinity at the μ receptor followed the stereochemical order l‐7 > ent‐l‐7 > ent‐u‐7 > u‐7 whereas for the tertiary amino alcohols the order l‐7 > u‐7 > ent‐l‐7 > ent‐u‐7 was found. The stereoisomers l‐7d and l‐7e of the tertiary amino alcohols were found to be the most active compounds the latter exhibiting a Ki value of 7.17 which is close to that of Morphine (Ki = 1.64). In an in vivo model, the Writhing Test, both compounds l‐7d and l‐7e displayed high analgetic activity.

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